Comparative Analysis of Pharmacophore Features and Quantitative Structure–Activity Relationships for CD38 Covalent and Non‐covalent Inhibitors

In the past decade, the discovery, synthesis, and evaluation for hundreds of CD38 covalent and non‐covalent inhibitors has been reported sequentially by our group and partners; however, a systematic structure‐based guidance is still lacking for rational design of CD38 inhibitor. Here, we carried out a comparative analysis of pharmacophore features and quantitative structure–activity relationships for CD38 inhibitors. The results uncover that the essential interactions between key residues and covalent/non‐covalent CD38 inhibitors include (i) hydrogen bond and hydrophobic interactions with residues Glu226 and Trp125, (ii) electrostatic or hydrogen bond interaction with the positively charged residue Arg127 region, and (iii) the hydrophobic interaction with residue Trp189. For covalent inhibitors, besides the covalent effect with residue Glu226, the electrostatic interaction with residue Arg127 is also necessary, while another hydrogen/non‐bonded interaction with residues Trp125 and Trp189 can also be detected. By means of the SYBYL multifit alignment function, the best CoMFA and CoMSIA with CD38 covalent inhibitors presented cross‐validated correlation coefficient values (q²) of 0.564 and 0.571, and non‐cross‐validated values (r²) of 0.967 and 0.971, respectively. The CD38 non‐covalent inhibitors can be classified into five groups according to their chemical scaffolds, and the residues Glu226, Trp189, and Trp125 are indispensable for those non‐covalent inhibitors binding to CD38, while the residues Ser126, Arg127, Asp155, Thr221, and Phe222 are also important. The best CoMFA and CoMSIA with the F12 analogues presented cross‐validated correlation coefficient values (q²) of 0.469 and 0.454, and non‐cross‐validated values (r²) of 0.814 and 0.819, respectively.     

苯胺衍生物对肝细胞毒性构效关系的量子化学研究

应用ＣＮＤＯ／２量子化学方法计算２８个苯胺衍生物分子的电子结构,探讨了药物分子的电子结构对肝细胞毒性三项指标的关系,结果得到了三个反映苯胺衍生物对肝细胞毒性的定量构效关系（ＱＳＡＲ）的回归方程：ｐＴＣ５０＝５．４１７＋０．６７９ＥＨＯＭＯ;ｐＳＤＨ＝－５．３８９－１．３５３ＳＱＲ－０．３４６ＥＨＯＭＯ;ｐＬＤＨ＝－６．０９４－１．５５６ＳＱＲ－０．３０６ＥＨＯＭＯ。根据所得的ＱＳＡＲ方程可预测化合     

Synthesis,Biological Evaluation,Mechanism of Action and Quantitative Structure–Activity Relationship Studies of Chalcones as Antibacterial Agents

Forty‐eight chalcone analogs were synthesized and their in vitro antibacterial activity against Staphylococcus aureus NCIM 5021, Bacillus subtilis NCIM 2718, Phaseolus vulgaris NCIM 2813, Escherichia coli NCIM 2931, Salmonella typhi 2501 and Enterobacter aerogenes NCIM 5139 were evaluated by microdilution broth assay. Quantitative structure–activity relationships were developed for all the cases (r ² = 0.68–0.79; = 0.58–0.78; q ² = 0.51–0.68; F = 13.02–61.51). Size, polarizability, electron‐donating/withdrawing and hydrophilic nature of the molecule determine the activity against these Gram‐positive and Gram‐negative bacteria. Staphylococcus aureus was the most and S. typhi was the least hydrophobic of these organisms. These chalcones act better against more hydrophobic organisms. The more active chalcones have log P between 1.5 and 3. Compound 24 , one of the most active compounds, was found to act by damaging the cell wall of S. aureus. Slimicidal activity of five of the most active compounds ( 24 , 31 , 32 , 34 and 37 ) was found to be in the range of 48–60% against S. aureus and 40–54% against E. coli. A correlation was observed among the hydrophobicity of the compounds, hydrophobicity of the bacterial cell surface and the antibacterial activity of the compound.     

Quantitative Structure–Activity Relationship Analysis of a Series of Human Renal Organic Anion Transporter Inhibitors

Organic anion transporters (OATs) have been proved to play important roles in the membrane transport of numerous potentially toxic xenobiotics, drugs, and endogenous metabolites. In general, OATs substrates can compete with one another for the transporter to mutually decrease renal secretion and thus delay the clearance and prolong the duration of action of each compound. Such interactions have the potential to bring about adverse outcomes for clinical cases. Therefore, it is very important to assess the molecular bioactivity to inhibit OATs during the development of new drugs and co‐administration. In this work, the relationships between 45 chemicals and their corresponding hOAT1 and hOAT3 inhibitory activities were analyzed. The quantitative structure–activity relationship (QSAR) model was developed by genetic algorithm and multiple linear regression method. The predictive power of the proposed model was strictly evaluated, and the applicability domain was also defined. The proposed models were robust and satisfactory and could provide a feasible and effective tool for hOAT1 or hOAT3 inhibitor screening.     

Physicochemical Characterization and Antioxidant Activity of Essential Oils of Guggul (Commiphora wightii) Collected from Madhya Pradesh

The present study reports physicochemical characterization and antioxidant activity of essential oils extracted from guggul (Commiphora wightii) exudates collected from different places in Madhya Pradesh, India. The guggul exudates were hydrodistilled for 3-4 h in Clevenger apparatus. The oil obtained was dried over anhydrous Na₂SO₄ and stored at 4° until testing. Before extraction of oils from the exudates, their % moisture and tristimulus values of the colors namely L (white-black), a (green-red) and b (blue-yellow) were determined. Physicochemical characterization of the extracted oils was carried out to determine their solubility, yield%, acid value (mg/KOH/g), saponification value (mg/KOH/g), ester value, iodine value (g/g), peroxide value (mEq/kg) and Fourier transformed infrared analyses. The storage-effect on the % moisture and tristimulus values of the colors of guggul exudates as also the % oil yield and physicochemical parameters of the essential oils extracted from them, were studied using three different packaging materials viz., local plastic, low density polyethylene (200 G) and high density polyethylene (200 G). The antioxidant potential of extracted oils was evaluated by free radical scavenging activity using 1,1-diphenyl-2-picryl hydrazyl assay.     

基于UPLC-QE-Orbitrap-MS的米邦塔仙人掌茎果化学成分表征及其抗氧化活性评价

目的 建立超高效液相色谱串联四极杆静电场轨道阱质谱方法(UPLC-Q-Exactive Orbitrap MS),对米邦塔仙人掌的叶状茎及果实化学成分进行表征,并对其抗氧化活性进行考察,初步探讨成分与活性的关系。方法 选择UPLC HSS T3 C18 (2.1 mm×10 mm, 1.8 μm) 色谱柱,以乙腈-0.1% 甲酸水为流动相梯度洗脱,流速为 0.2 mL.min-1;采用加热电喷雾离子源(HESI),正、负离子模式分别进行一级、二级质谱数据采集;采用数据库和文献报道对米邦塔仙人掌叶状茎及果实的化学成分进行表征。采用DPPH、羟自由基(.OH)和超氧阴离子自由基(.O2-)清除能力测试方法,对米邦塔仙人掌叶状茎及果实的抗氧化活性进行考察。结果 从米邦塔仙人掌的叶状茎及果实中共表征出39种化合物,其中酚酸类22个,黄酮类13个,其他成分4个。米邦塔仙人掌叶状茎及果实均具有一定的抗氧化能力,米邦塔仙人掌果实对DPPH的清除能力强于叶状茎,而叶状茎对.OH清除能力稍强于果实,叶状茎皮和果皮清除能力相当,果汁对.O2-清除能力最强,米邦塔仙人掌的抗氧化活性与其富含的酚酸类成分密切相关。结论 本研究建立了一种快速、准确、可靠的米邦塔仙人掌茎果化学成分的鉴别方法,为米邦塔仙人掌资源的综合开发利用提供了科学依据。     

Synthesis,Evaluation of Pharmacological Activities and Quantitative Structure–Activity Relationship Studies of a Novel Group of bis(4‐Nitroaryl‐1,4‐dihyropyridine)

Voltage‐dependent calcium channels are crucial targets for a wide range of clinically active pharmacological agents. From these agents, 1,4‐dihydropyridines constitute a group of small organic compounds are based on a core pyridine structure which can both block and enhance calcium currents. They are considered specific for L‐Type calcium channels; however, other channel types, and in particular certain T‐Type channels, may show sensitivity to dihydropyridine compounds. In this study, we synthesized a novel group of bis‐1,4‐dihydropyridines using the procedure reported by Dagnino that involved the condensation of n‐alkyl diacetoacetate (n = 2–7) with methyl‐3‐aminocrotonate and nitrophenylaldehyde. The synthesis was run under two conditions: (i) reflux and (ii) microwave. Calcium channels antagonist activity were determined in vitro using guinea‐pig ileum longitudinal smooth muscle assay. Synthesis of these compounds was confirmed with 1H‐NMR, IR and mass spectrometry. Then IC₅₀ of them are calculated and compared with Nifedipine. Finally, the result of this pharmacological assay was used in quantitative structure–activity relationship studies utilizing multiple linear regression analysis. Most of these compounds are less active compared with Nifedipine. Decrease in activity is the result of increase in steric hindrance. The quantitative structure–activity relationship study indicates that the activity is related to the electrostatic and topological parameters and the distance between two C5‐esteric groups of 1,4‐dihydropyridine rings.